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We have analyzed the self-reactive repertoires of IgM and IgG Abs in the serum of 19 patients with hyper-IgM syndrome (HIM) by means of a quantitative immunoblotting technique that allows for a quantitative comparison of Ab repertoires in health and disease by multiparametric statistical analysis. Normal tissue extracts of liver, lung, stomach, and kidney were used as sources of self Ags. Extracts of Pseudomonas aeruginosa and Staphylococcus epidermidis were used as sources of nonself Ags. We demonstrate a significant bias in repertoires of reactivities of IgM of patients with HIM with self Ags. Ab repertoires of IgM toward nonself Ags did not differ, however, between patients and controls. No difference was found between IgM repertoires of untreated patients and those of patients receiving substitutive treatment with i.v. IgG. IgG in the serum of HIM patients lacked reactivity with self Ags, although it exhibited a pattern of reactivity with nonself Ags that was similar to that of IgG of healthy controls. The data demonstrate that functional CD40-CD40 ligand interactions are essential for the selection of natural self-reactive B cell repertoires.

X-linked hyper-IgM syndrome (X-HIM) is an immunodeficiency caused by mutations in the gene encoding the CD40 ligand (CD40L). A database (CD40Lbase) of CD40L mutations has now been established, and the resultant information, together with other mutations reported elsewhere in the literature, is presented here.

X-linked immunodeficiency with hyperimmunoglobulinemia M (XHM) reflects an impairment of the immunoglobulin (Ig) heavy (H) chain class switch of B lymphocytes from IgM to IgG and IgA. XHM is recessive; female carriers manifest normal IgG and IgA production. Due to random X chromosome inactivation in all somatic cells of females, about half of the lymphocytes of XHM carriers are not able to express an intact XHM gene. An intrinsic defect of the Ig H chain class switch mechanism in XHM B lymphocytes would thus lead to a skewed X chromosome inactivation pattern in the IgG- and IgA-expressing B lymphocytes of female carriers. IgM-, IgG- and IgA-expressing B lymphoblastoid cells (BLC) were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells of two female XHM carriers. In an analysis of differential methylation of the polymorphic DXS255 loci, random X chromosome inactivation patterns were found in populations of T lymphocytes, in IgM-expressing B lymphocytes and in IgG- or IgA-expressing B lymphocytes. The heterogeneity of Ig H chain rearrangements and the Ig light chain usage in the IgA- or IgG-expressing BLC clones that had inactivated the X chromosome which carries the intact XHM gene and in BLC clones with the homologous X chromosome inactivated were similar. The results indicated that the intrinsic Ig H chain class switch mechanism in XHM B lymphocytes is fully intact. We conclude that the XHM gene encodes a class switch inducer that is transferred to B lymphocytes.

The gene involved in X-linked immunodeficiency with hyperimmunoglobulinemia M (XHM) was localized by the use of nine restriction fragment length polymorphic (RFLP) markers covering the entire X chromosome. Multipoint linkage analysis of RFLP data obtained in a three generation XHM pedigree indicates the Xq24-q27 area around the DXS42 RFLP locus as the most likely localization of the XHM locus.